(6R,12aR)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione (a compound of Formula I), also known as tadalafil, is a potent, selective, and reversible inhibitor of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase type 5 enzyme (cGMP specific PDE5).
The biochemical, physiological, and clinical effects of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase (cGMP-specific PDE) inhibitors suggest their utility in a variety of disease states in which modulation of smooth muscle, renal, hemostatic, inflammatory, and/or endocrine function is desired. Type 5 cGMP-specific phosphodiesterase (PDE5) is the major cGMP hydrolyzing enzyme in vascular smooth muscle and its expression in penile corpus cavernosum has been reported (Taher et al., J. Urol., 285A:149 (1993)). PDE5 is an attractive target in the treatment of sexual dysfunction (Murray, Drug News and Perspectives, 6 (3):150-156 (1993)).
U.S. Pat. No. 5,859,006 (hereinafter the '006 patent) discloses a class of β-carboline compounds, which are useful in the treatment of conditions wherein inhibition of PDE5 is desired. The '006 patent discloses two synthetic pathways for preparation of tadalafil. Path (I) involves Pictet-Spengler reaction of D-tryptophan methyl ester with piperonal leading to the formation of a mixture of cis- and trans-tetrahydro β-carboline intermediates of Formula II and IIB (hereinafter the cis-intermediate of Formula II and trans-intermediate of Formula IIB respectively) in a 3:2 ratio.

The cis-intermediate of Formula II is then converted to tadalafil in two steps. However, the '006 patent process involves longer reaction times and the yield of the cis-intermediate of Formula II (the desired isomer) is poor and, additionally, it has to be separated from the trans-intermediate of Formula IIB. Moreover, the Pictet-Spengler reaction in path (I) described above, is carried out in the presence of trifluoroacetic acid which is a highly corrosive and hazardous reagent. Path (II) starts with the reaction of D-tryptophan methyl ester with piperonoyl chloride and involves four steps to prepare the cis-intermediate of Formula II. Though this is a better yielding process, it is cumbersome as it involves many synthetic steps.
WO 2004/011463 discloses a process for preparation of the cis-intermediate of Formula II wherein D-tryptophan methyl ester hydrochloride is reacted with piperonal in isopropanol. The use of isopropanol in the above reaction requires control of the reaction temperature on account of its low boiling point and low flash point. Isopropanol may also be contaminated with peroxides which can cause undesired side reactions. As a result, it is desirable to employ solvents which are easier to handle.
WO 2005/068464 discloses a process for preparation of the cis-intermediate of Formula II wherein the reaction of D-tryptophan methyl ester hydrochloride with piperonal is carried out in the presence of molecular sieves.
U.S. Patent Application No. 2006/0276652 discloses a process for preparation of the cis-intermediate of Formula II wherein D-tryptophan methyl ester hydrochloride is reacted with piperonal in ethyl acetate in the presence of trifluoroacetic acid.
U.S. Patent Application No. 2006/0258865 discloses a process for preparation of the cis-intermediate of Formula II wherein D-tryptophan methyl ester hydrochloride is reacted with piperonal in dimethyl acetamide with or without the use of a dehydrating agent. The work-up process involves additional acid-base treatment which can be done away with.